Heterocyclic thioureas, isothioureas, guanidines and nitromethylene-amidines

ABSTRACT

The compounds are C 2  -C 8  straight chain alkanes terminally substituted, symmetrically or unsymmetrically, by N-(N&#39;-substituted guanidino), N-(N&#39;,N&#34;-disubstituted guanidino), N-(N&#39;-substituted thioureido), N-(nitromethylene amidino) or S-(N-substituted isothioureido)groups. Two compounds of the invention are 1,3-bis-[N&#39;-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]propane and 1,3-bis-[S-(N-2-(5-methyl-4-imidazolylmethylthio)ethyl)isothioureido]propane. The compounds of this invention are inhibitors of H-2 histamine receptors.

This is a division of application Ser. No. 070,950 now U.S. Pat. No.4,301,165 filed Aug. 30, 1979, which is a division of application Ser.No. 941,836 filed Sept. 11, 1978 now U.S. Pat. No. 4,197,305, which is adivision of application Ser. No. 836,626 filed Sept. 26, 1977 now U.S.Pat. No. 4,137,319, which is a division of application Ser. No. 678,564filed Apr. 20, 1976 now U.S. Pat. No. 4,070,472, which is a division ofapplication Ser. No. 542,971 filed Jan. 22, 1975 now U.S. Pat. No.3,968,227.

This invention relates to new compounds having pharmacological activity.These compounds are inhibitors of H-2 histamine receptors. In addition,this invention relates to pharmaceutical compositions comprising thesecompounds and to methods of inhibiting H-2 histamine receptors byadministering these compounds. The compounds of this invention can existas the addition salts but, for convenience, reference will be madethroughout this specification to the parent compounds.

Many of the physiologically active substances within the animal body, inthe course of their activity, combine with certain specific sites knownas receptors. Histamine is a compound which is believed to act in thisway, but since the actions of histamine fall into more than one type, itis believed that there is more than one type of histamine receptor. Thereceptors involved in the type of action of histamine which is blockedby drugs commonly called "antihistamines", of which mepyramine is atypical example, have been designated as H-1 histamine receptors (Ashand Schild, Brit. J. Pharmac. Chemother. 27, 427, (1966)). The receptorsinvolved in the type of action of histamine which is not blocked by"antihistamines" such as mepyramine have been designated as H-2histamine receptors and burimamide has been defined as an H-2 histaminereceptor inhibitor (Black et al. Nature 236, 385 (1972)). Thus, H-2bistamine receptors may be defined as those histamine receptors whichare not inhibited by mepyramine but are inhibited by burimamide.

Inhibitors of H-2 histamine receptors are of utility in inhibitingactions of histamine which are not inhibited by "antihistamines". Theyare useful, for example, as inhibitors of gastric acid secretion.

The compounds of this invention are H-2 histamine receptor inhibitors.These compounds are represented by the following general formula:##STR1## wherein R₁ and R₂, which may be the same or different, eachrepresent a grouping of the structure shown in Formula II: ##STR2##wherein Het is a nitrogen containing 5 or 6 membered heterocyclic ringsuch as imidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole,pyrazole, triazole, thiadiazole, pyrimidine, pyrazine or pyridazinewhich is optionally substituted by lower alkyl, hydroxyl, halogen oramino; Z is sulphur or a methylene group; m is 0, 1 or 2; n is 2 or 3and the sum of m and n is 3,4, or when Y is other than hydrogen, methyl,or hydroxyl, 2; X₁ and X₂, which may be the same or different, are eachsulphur, CHNO₂ or NY wherein Y is hydrogen, hydroxy, lower alkyl, cyano,CONH₂ or SO₂ R₃ ; R₃ is lower alkyl, substituted or unsubstituted aryl,preferably phenyl or tolyl, trifluoromethyl or amino; W is NH, and whenX₁ and X₂ are NH W may also be sulphur; and q is an integer from 2 to 8;or a pharmaceutically acceptable acid addition salt thereof.

It will be understood that the structure illustrated in Formula I isonly one of several representations and that other tautomeric forms arealso covered by the present invention.

Throughout the present specification and claims by the term `loweralkyl` we mean an alkyl group containing from 1 to 4 carbon atoms.

In a preferred group of compounds R₁ and R₂ are the same. R₁ and/or R₂are preferably Het--CH₂ S(CH₂)₂ --and it is particularly preferable thatHet is imidazole, optionally substituted by methyl or halogen; thiazole;or isothiazole or pyridine optionally substituted by methyl, hydroxyl orhalogen.

Likewise it is preferred that X₁ and X₂ be the same. Useful series ofcompounds are those wherein X₁ and X₂ are both sulphur, wherein X₁ andX₂ are both NY and Y is hydrogen or cyano, and wherein X₁ and X₂ areboth CHNO₂.

It is preferred that q be from 2 to 4, particularly 3. Examples ofspecific compounds falling within the scope of the present inventionare:

1,2-bis-[N'-(2-(5-methyl-4-imidazolymethylthio)ethyl)thioureido]-ethane

1,3-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)thioureido]-propane

1,4-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)thioureido]-butane

1,3-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]propane

1,3-bis-[N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]propane

1,3-bis-[S-(N-2-(5-methyl-4-imidazolylmethylthio)ethyl)isothioureido]propane

The compounds of Formula I wherein W is NH, R₂ is the same as R₁, X₁ andX₂ are both X₃, X₃ being sulphur, CHNO₂, NH, NCN, or NSO₂ R₄, R₄ beinglower alkyl, substituted or unsubstituted aryl, preferably phenyl ortolyl, or trifluoromethyl, may be prepared by treating an excess(preferably two equivalents) of a compound of Formula III: ##STR3##wherein E is hydrogen or ##STR4## X₃ being as defined above and A beinglower alkyl, with a compound of Formula IV: ##STR5## wherein both thegroups B are hydrogen when E is ##STR6## and are ##STR7## when E ishydrogen, X₃ and A being as defined above.

Preferably this reaction is carried out in a solvent, such as ethanol,isopropanol or pyridine. When X₃ is NCN or NSO₂ R₄ the reaction may bemodified by first adding a silver salt, such as silver nitrate, to thereactant bearing the ##STR8## function, removing the silver alkylmercaptide which is formed, and then adding the reacting amine.

Compounds of Formula III wherein E is ##STR9## and X₃ is sulphur may beprepared from an amine of formula R₁ NH₂ by successive reaction thereofwith carbon disulphide and an alkylating agent, such as methyl iodide.

Compounds of Formula III wherein E is ##STR10## and X₃ is CHNO₂, NCN,or, NSO₂ R₃ may be prepared by treating a compound of Formula V##STR11## wherein X₃ is CHNO₂, NCN, or NSO₂ R₄ and A is alkyl, with anequivalent amount of an amine of formula R₁ NH₂. This reaction isconveniently carried out in a solvent such as ethanol.

The compounds of Formula III wherein E is ##STR12## and X₃ is NH areconveniently prepared by alkylating a thiourea of formula R₁ NHCSNH₂.These thioureas may be prepared by treating an amine of formula R₁ NH₂with benzoyl isothiocyanate, and hydrolysing the product under alkalineconditions.

The compounds of Formula IV wherein both the groups are ##STR13## may beprepared from the corresponding diamines by methods similar to thosedescribed above for the preparation of compounds of Formula III whereinY is ##STR14##

Mild acid hydrolysis of the compounds of Formula I wherein X₁ and X₂ areboth NCN yields the compounds of Formula I wherein X₁ and X₂ are bothNCONH₂. Acid hydrolysis of the compounds of Formula I wherein X₁ and X₂are both NCN yields the compounds of Formula I wherein X₁ and X₂ areboth NH.

The compounds of Formula I wherein X₁ and X₂ are both NHSO₂ NH₂ may beprepared from the corresponding compounds of Formula I wherein W is NHand X₁ and X₂ are both NH by reaction of the latter compounds withN-piperidylsulphamide. This reaction is conveniently carried out inboiling ethanol.

The above methods of synthesis may be modified in produce thosecompounds wherein W=NH and X₁ and X₂ and/or R₁ and R₂ are different. Inthis case the starting material is conveniently the diamine of FormulaIV, wherein both the groups B are hydrogen, which is first treated witha suitable reagent to form a mono-protected diamine of Formula VI:##STR15## wherein q has the above significance and Q is a suitableprotecting group e.g., an acid labile protecting group such as benzoylor formyl. Reaction of this compound with one equivalent of a compoundof Formula III wherein E is ##STR16## gives the compound of Formula VII:##STR17## wherein R₁, X₃, Q and q have the above significance. Treatmentof this compound with acid followed by reaction with a substance ofFormula VIII: ##STR18## wherein A, R₂ and X₂ have the above significanceand R₂ and/or X₂ are not identical to R₁ and/or X₁ in Formula VIIresults in the required compound of Formula I wherein R₁ and R₂ and/orX₁ and X₂ are different. Alternatively, the amine of Formula VI may beconverted into a compound of Formula IX: ##STR19## wherein Q, q, X₃ andS have the above significance, by the general methods described abovefor the preparation of compounds of Formula IV wherein E is ##STR20##Treatment of a compound of Formula IX with an amine of formula R₁ NH₂,R₁ being as defined above, gives a compound of Formula VII which may beconverted into a compound of Formula I by successive treatment with acidand a compound of Formula VIII as described above.

It will be appreciated that the above processes for the production ofcompounds of Formula I wherein W is NH involve the reaction between acompound of Formula III and a compound of Formula X ##STR21## wherein Bis hydrogen when E is ##STR22## and B is ##STR23## when E is hydrogen, Abeing lower alkyl and X₃ being sulphur, CHNO₂, NH, NCN or NSO₂ R₄, R₄being lower alkyl, substituted or unsubstituted aryl or trifluoromethyl,q is as defined in Formula I and G is B or a group --CX₂ NHR₂ wherein X₂and R₂ are as defined in Formula I.

The compounds of Formula I wherein X₁ and/or X₂ are NY and Y is hydroxyor lower alkyl may be prepared from the corresponding thiourea ofFormula I wherein X₁, and/or X₂ is sulphur, and neither X₁ nor X₂ are NHby alkylating the thiourea, e.g., by treatment with hydrogen chloride inmethanol or methyl iodide, and then treating the resulting compound withhydroxylamine or a lower alkylamine, respectively.

The compounds of Formula I wherein X₁ and/or X₂ are NCN mayalternatively be prepared from the corresponding thiourea of Formula Iwherein X₁ and/or X₂ is sulphur, and neither X₁ nor X₂ are NH, byalkylation and treatment of the product with cyanamide and a strong basesuch as potassium t-butoxide.

The compounds of Formula I wherein X₁ or X₂ are N.CN may also beprepared from the corresponding compounds of Formula I wherein X₁ or X₂are sulphur by reaction of the latter with a heavy metal salt ofcyanamide such as lead, mercury or cadmium cyanamide in a solvent suchas acetonitrile and/or dimethylformamide.

The compounds of Formula I wherein W is sulphur and X₁ and X₂ are bothNH may be prepared by alkylating a thiourea of Formula R₁ NHCSNH₂wherein R₁ is as defined in Formula I with a dihalo compound of formulaHal--(CH₂)_(q) --Hal, wherein Hal represents chlorine, bromine oriodine. Preferably the reaction is carried out on an acid addition saltof the thiourea, Hal is bromine and the reaction is carried out in asuitable solvent such as ethanol.

The compounds of Formula I are inhibitors of H-2 histamine receptors,that is they are inhibitors of the actions of histamine which are notblocked by "antihistamines" such as mepyramine but are blocked byburimamide. For example, the compounds of this invention have been foundto inhibit selectively the histamine-stimulated secretion of gastricacid from the lumen-perfused stomachs of rats anaesthetized withurethane, at doses of from 0.5 to 256 micromoles per kilogramintravenously. This procedure is described in the above mentioned paperof Ash and Schild. Also, the activity of these compounds as H-2histamine receptor inhibitors is demonstrated by their antagonism toother actions of histamine which, according to the above mentioned paperof Ash and Schild, are not mediated by H-1 histamine receptors. Forexample, the H-2 histamine receptor inhibitory activity of the compoundsof this invention is demonstrated by antagonism of the actions ofhistamine in stimulating isolated guinea pig atrium and inhibitingcontractions in the isolated rat uterus.

The compounds of this invention inhibit the secretion of gastric acidstimulated by pentagastrin or by food. The level of activity found forthe compounds of the present invention is illustrated by the effectivedose range in the anaesthetised rat, as mentioned above of from 0.5 to256 micromoles per kilogram, intravenously. Many of the compounds of thepresent invention produce a 50% inhibition in this test at a dose offrom 1 to 10 micromoles per kilogram.

For therapeutic use, the pharmacologically active compounds of thepresent invention will normally be administered as a pharmaceuticalcomposition comprising as the or an essential active ingredient at leastone such compound in the basic form or in the form of an addition saltwith a pharmaceutically acceptable acid and in association with apharmaceutical carrier therefor. Such addition salts include those withhydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and mayconveniently be formed from the corresponding bases of Formula I bystandard procedures, for example by treating the base with an acid in alower alkanol or by the use of ion exchange resins to form the requiredsalt either directly from the base or from a different addition salt.Pharmaceutical compositions comprising a pharmaceutical carrier and acompound of Formula I or a pharmaceutically acceptable acid additionsalt thereof and methods of inhibiting H-2 histamine receptors whichcomprise administering a compound of Formula I or a pharmaceuticallyacceptable acid addition salt thereof are also objects of thisinvention. The pharmaceutical carrier employed may be, for example,either a solid or liquid. Exemplary of solid carriers are lactose, terraalba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid and the like. Exemplary of liquid carriers are syrup,peanut oil, olive oil, water and the like.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg to about 1 g. If a liquid carrier is used, thepreparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as in an ampoule, or an aqueousor non-aqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniques,involving procedures such as mixing, granulating and compressing ordissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the compositions in aneffective amount to inhibit H-2 histamine receptors. The route ofadministering may be orally or parenterally. Preferably, each dosageunit will contain the active ingredient in an amount of from about 50 mgto about 250 mg. The active ingredient will preferably be administeredin equal doses one to six times per day. The daily dosage regimen willpreferably be from about 150 mg to about 1500 mg. Otherpharmacologically active compounds may in certain cases be included inthe composition. Advantageously the composition will be made up in adosage unit form appropriate to the desired mode of administration, forexample as a tablet, capsule or injectable solution.

The invention is illustrated but in no way limited by the followingexamples wherein all temperatures are in degrees Centigrade:

EXAMPLE 11,2-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)thioureido]ethane

(a) A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (10.2g) in ethanol (75 ml) was added slowly, with stirring, to carbondisulphide (200 ml). The mixture was set aside overnight at roomtemperature and the solid formed was collected and recrystallised fromaqueous isopropyl alcohol to affordN-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]dithiocarbamic acid (9.8g)., m.p. 127°-129°.

(Found: C, 38.6: H, 5.5: N, 16.7: C₈ H₁₃ N₃ S₃ requires: C, 38.8: H,5.3: N, 17.0%).

(b) Methyl iodide (4.0 g) was added to a suspension of thedithiocarbamic acid (7.0 g) in methanol (100 ml). After stirring at roomtemperature for 1.5 hours, a solution was obtained. Concentrationfollowed by recrystallisation of the residue from isopropylalcohol-ether gaveS-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-dithiocarbamatehydriodide (8.6 g), m.p. 167°-169°.

(Found: C, 27.7: H, 4.0: N, 10.8: I, 32.9: C₉ H₁₅ N₃ S₃.HI requires: C,27.8: H, 4.1: N, 10.8: I, 32.6%).

(c) A solution of the above hydriodide (5.5 g) in absolute ethanol (60ml) was added to a solution of sodium (0.325 g) in ethanol (100 ml).Following filtration, a solution of 1,2-diaminoethane (0.424 g) inethanol (30 ml) was added to the filtrate which was heated under refluxfor 24 hours. Following concentration, the residual oil was purified byrepeated reprecipation from isopropanol with water and from isopropanolwith ether. Finally chromatographic purification on a column of silicagel with ethyl acetate-ethanol (3:1) as eluant and final precipitationfrom isopropanol-ether gave the title compound as a colourless lowmelting solid, containing approximately 4.5% diethyl ether.

The NMR spectrum of a solution in ² H₆ dimethyl sulphoxide, recorded at60 mHZ showed the following resonances:

    ______________________________________                                        --NH--CS--NH--: multiplet                                                                              integral, 6.0 protons:                               at δ7.7                                                                 imidazole-2-H: singlet at δ7.48                                                                  calculated, 6.0 protons.                             imidazole-CH.sub.2 --: singlet,                                                                        integral, 12.4 protons:                              at δ3.68                                                                --CH.sub.2 --NH--CS--NH--CH.sub.2 :                                                                    calculated, 12.0 protons.                            multiplet at δ3.5                                                       --CH.sub.2 CH.sub.2 S--: multiplet, at δ2.62                                                     integral could not be                                                         measured                                             imidazole-CH.sub.3 : singlet, at δ2.13:                                                          the integral was used as                                                      the internal standard,                                                        equal to 6.0 protons.                                ______________________________________                                    

The spectrum also showed the presence of 4.5% w/w diethyl ether.

(Found: C, 45.6: H, 6.7: C₁₈ H₃₀ N₈ S₄ +4.5% C₄ H₁₀ O requires: C, 45.3:H, 6.5%)

EXAMPLE 2 1,3-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)thioureido]propane

S-Methyl-N'-[2-(5-methyl-4-imidazolyl)methylthio)ethyl]dithiocarbamatehydriodide (7.8 g) was converted into the free base with sodium (0.46 g)in ethanol. Reaction with 1,3-diaminopropane (0.74 g) and purificationby the method described in Example 1 gave the product which was furtherpurified by successive treatment of a solution in methanol-water withcationic and anionic exchange resins. Following precipitation fromisopropanol-ether, the title compound was obtained as a colourless lowmelting solid containing approximately 4.5% diethyl ether.

The NMR spectrum of a solution in ² H₆ dimethyl sulphoxide recorded at60 mHZ showed the following resonances.

    ______________________________________                                        --NH--CS--NH--: triplet δ7.62                                                                      integral, 7.0 protons:                                                        calculated 6.0                                     imidazole-2H: singlet δ7.42                                                                        protons.                                           imidazole-CH.sub.2 : singlet, δ3.67                                                                integral 13.0 protons                                                         (including H.sub.2 O in                                                       NMR solvent):                                      CH.sub.2 NH--CSNH--CH.sub.2 : multiplet, δ3.5                                                      calculated 12.0.                                   CH.sub.2 --CH.sub.2 --S: triplet δ2.60                                                             integral 5.0 pro-                                                             tons (including                                                               DMSO-d.sub.5):                                                                calculated 4.0.                                    imidazole-CH.sub.3 : singlet δ2.13:                                                                The integral was                                                              used as the internal                                                          standard, equal to                                                            6.0 protons.                                       CH.sub.2 CH.sub.2 CH.sub.2 : multiplet δ1.7:                                                       integral 2.0 protons:                                                         calculated 2.0                                                                protons.                                           ______________________________________                                    

The spectrum also showed the presence of 4.5% weight/weight diethylether.

(Found: N, 21.7: S, 24.6; C₁₉ H₃₂ N₈ S₄ +4.5% C₄ H₁₀ O requires: N,21.4: S, 24.5%)

EXAMPLE 31,4-bis-[N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl)thioureido]butane

S-Methyl-N'-[2-(5-methyl-4-imidazolyl)methylthio)ethyl]dithiocarbamatehydriodide (5.5 g) was converted into the free base with sodium inethanol. Reaction with 1,4-diaminobutane (0.63 g) and subsequentpurification by the method described in Example 1 afforded the titlecompound as a low-melting colourless solid containing approximately 5.9%diethyl ether.

The NMR spectrum of a solution in ² H₆ dimethyl sulphoxide recorded at60 mHZ showed the following resonances.

    ______________________________________                                        --NH--CS--NH--: multiplet, δ7.6                                                                  integral 5.8 protons:                                imidazole-2H: singlet, δ7.47                                                                     calculated, 6.0 protons.                             imidazole-CH.sub.2 : singlet, δ3.69                                                              integral 12.6 protons:                               CH.sub.2 CH.sub.2 N--: multiplet, δ3.5                                                           calculated, 12.0 protons.                            CH.sub.2 CH.sub.2 S: triplet, δ2.63                                                              The integral could                                                            not be measured.                                     CH.sub.3 --Imidazole: singlet, δ2.15:                                                            The integral was used as                                                      the internal standard                                                         equal to 6.0 protons.                                CH.sub.2 --(CH.sub.2).sub.2 --CH.sub.2 : multiplet, δ1.5                                         integral 4.2 protons                                                          calculated 4.0 protons.                              ______________________________________                                    

The spectrum also showed the presence of 5.9% weight/weight diethylether.

(Found: C, 47.6: H, 7.2; C₂₀ H₃₄ N₈ S₄ +5.9% C₄ H₁₀ O requires: C, 47.7:H, 7.1%)

EXAMPLE 41,5-bis-[N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl)thioureido]pentane

The reaction ofS-methyl-N'-[2-(5-methyl-4-imidazolyl)methylthio)ethyl]dithiocarbamatewith 1,5-diaminopentane by the method described in Example 1 gave thetitle compound as an amorphous powder which contained residual ether andwater.

(Found: C, 47.5: H, 7.2: N, 19.9: S, 23.3: C₂₁ H₃₆ N₈ S₄ +2% C₄ H₁₀ O+2%H₂ O requires: C, 47.1: H, 7.1: N, 20.3: S, 23.3%).

The NMR spectrum of a solution in ² H₆ dimethyl sulphoxide recorded at60 mHZ showed the following resonances.

    ______________________________________                                        --NH--CS--NH--: multiplet,                                                                             integral 5.3 protons                                 435-465 H.sub.Z                                                               imidazole-2H: singlet, δ7.47                                                                     calculated, 6.0 protons                              imidazole-CH.sub.2 : singlet, δ3.68                                                              integral 12.3 protons                                CH.sub.2 CH.sub.2 S + CH.sub.2 CH.sub.2 N:                                    multiplet, 185-235 H.sub.Z                                                                             calculated 12.0 protons                              CH.sub.2 --CH.sub.2 --S: multiplet,                                                                    integral 4.5 protons                                 140-175 H.sub.Z          (including DMSO-d.sub.5)                                                      calculated 4 protons                                 CH.sub.3 --Imidazole: singlet, δ2.15:                                                            The integral was used                                                         as the internal                                                               standard equal to                                                             6 protons.                                           CH.sub.2 (CH.sub.2 --CH.sub.2).sub.2 NH multiplet,                                                     Integral 5.3 protons                                 70-110 H.sub.Z           calculated 6.0 protons                               ______________________________________                                    

EXAMPLE 51,3-bis-[N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl)guanidino]propane

(i) A solution of N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea(2.29 g) and methyl iodide (1.56 g) in methanol (5 ml) was kept at roomtemperature for 18 hours affordingS-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiouroniumiodide (2.3 g), m.p. 128°-131°. The iodide was converted into thecorresponding sulphate by ion-exchange on an ion-exchange resin (IRA401) in the sulphate form.

(ii) 1,3-Diaminopropane (0.37 g) was added to a solution ofS-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiouroniumsulphate (2.93 g) in water (10 ml) and the mixture was heated underreflux for 2 hours. Following concentration the residue was convertedinto the picrate with an aqueous solution of sodium picrate.Recrystallisation from ethanol afforded the title compound as thedipicrate (1.1 g) m.p. 114°-6°.

(Found: C, 40.3: H, 4.2: N, 23.7: S, 6.9; C₁₉ H₃₆ N₁₀ S₂.2 C₆ H₃ N₃ O₇requires: C, 40.3; H, 4.4; N, 24.2; S, 6.9%).

The dipicrate was dissolved in aqueous methanol and treated withion-exchange resin IRA 400 (Cl⁻) to afford the dihydrochloride.

(Found: Cl, 12.8% C₁₉ H₃₆ N₁₀ S₂. 2HCl requires: Cl, 13.1%).

EXAMPLE 61,2-bis-[N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl)guanidino]ethane

The reaction of 1,2-diaminoethane (0.60 g) withS-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiouroniumsulphate (5.86 g) by the method described in Example 5 afforded thetitle compound which was isolated as the dipicrate (3.5 g), m.p.201°-203°.

(Found: C, 39.5: H, 4.3: N, 24.2: S, 6.9; C₁₈ N₃₄ N₁₀ S₂. 2 C₆ H₃ N₃ O₇requires: C, 39.6: H, 4.2: N, 24.6: S, 7.0%).

EXAMPLE 71,5-bis-[N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl)guanidino]pentane

The reaction of 1,5-diaminopentane (0.43 g) withS-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethylthiouronium]sulphate(2.52g) by the method described in Example 5 afforded the title compoundwhich was isolated as the dipicrate (1.8 g) m.p. 115°-120°.

EXAMPLE 81,3-bis-[N'-Cyano-N"-(2-(5-methyl-4-imidazolyl)methylthio)ethyl)guanidino]propane

(a) A mixture of 1,3-bis-[N-cyano-S-methyl-isothioureido]propane (1.67g) and 5-methyl-4-(2-aminoethyl)imidazole (2.36 g) in anhydrous pyridine(40 ml) was heated under reflux for 8 hours. Following concentration andtrituration with acetonitrile-water (2:1) the product waschromatographed on a column of silica with elution by a mixture ofchloroform (85 parts) and methanolic ammonia (15 parts) to yield thetitle compound.

The NMR spectrum of a solution in ² H₆ dimethyl sulphoxide showed thefollowing resonances.

    ______________________________________                                        imidazole-2H;       Singlet, δ7.56                                      N--H;               multiplet, δ7.22                                    imidazole-CH.sub.2 ;                                                                              singlet, δ3.68                                      CH.sub.2 CH.sub.2 NH;                                                                             multiplet, δ3.25                                    CH.sub.2 CH.sub.2 S;                                                                              multiplet, δ2.65                                    CH.sub.3 --imidazole;                                                                             singlet, δ2.16                                      CH.sub.2 CH.sub.2 CH.sub.2 ;                                                                      multiplet, δ1.75                                    ______________________________________                                    

(b) Lead cyanamide (3.0 g) was added to1,3-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)thioureido]propane(2.5 g) in acetonitrile. Dimethylformamide was added and the mixture wasstirred and boiled under reflux for 24 hours. The mixture was filtered,concentrated and purified by chromatography to give the title compound.

(c) A mixture of1,3-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)thioureido]propane(10.3 g) 55% hydriodic acid (12.2 ml) methyl iodide (5.3 ml) andmethanol was boiled under reflux for 4 hours and, evaporated to drynessto give1,3-bis-[S-methyl-N'-(2-(5-methyl-4-imidazolylmethylthio)-ethyl)isothioureido]propanetetrahydriodide. This intermediate (2.05 g) was treated with potassiumt-butoxide (1.5 g) and cyanamide (0.5 g) in anhydrous t-butanol and themixture was boiled under reflux overnight, filtered, and purified bychromatography to give the title product.

EXAMPLE 91,2-bis-[S-(N-2-(5-Methyl-4-imidazolylmethylthio)ethyl)isothioureido]ethanetetrahydrobromide

A solution of N-[2-(5-methyl-4-imidazolyl)methylthio)ethyl]thiourea(3.45 g) in isopropyl alcohol (25 ml) was cooled and 48% aqueoushydrobromic acid (2.54 g) added. The hydrobromide salt was precipitatedwith excess ether and dissolved in ethanol (25 ml). 1,2-Dibromoethane(1.5 g) was added and the solution obtained was heated under reflux for24 hours. Concentration and crystallisation from methanol-isopropylalcohol afforded the title compound (2.2 g) m.p. 215°-217°.

(Found: C, 26.7: H, 4.1: N, 13.8; S, 15.8: Br, 39.6: C₁₈ H₃₀ N₈ S₄. 4HBr requires: C, 26.7: H, 4.2; N, 13.8: S, 15.8: Br, 39.4%).

EXAMPLE 101,3-bis-[5-(N-2-(5-Methyl-4-imidazolylmethylthio)ethyl)isothioureido]propan

The reaction of N-[2-(5-methyl-4-imidazolyl)methylthio)ethyl]thioureahydrobromide (from 3.45 g of the thiourea) with 1,3-dibromopropane bythe method described in Example 9 afforded the title compound which wasisolated as its tetrapicrolonic acid salt (4.75 g), m.p. 165°-167° (fromnitromethane-ethanol).

(Found: C, 45.2: H, 4.3: N, 21.5: S, 7.8%. C₁₉ H₃₂ N₈ S₄. 4 C₁₀ H₈ N₄ O₅requires: C, 45.5: H, 4.1: N, 21.6: S, 8.2%). The tetrapicrolonate saltwas suspended in aqueous methanol and treated with ion-exchange resinIRA 401 (Cl⁻ form) and the suspension stirred for 3 hours. Concentrationafforded the tetrahydrochloride (0.9 g), m.p. approx. 110°

(Found: C, 35.1: H, 6.0: C₁₉ H₃₂ N₈ S₄. 4 HCl requires: C, 35.3: H,5.9%).

EXAMPLE 111,4-bis-[S-(N-2-(5-Methyl-4-imidazolylmethylthio)ethyl)isothioureido]butanetetrahydrobromide

The reaction of N-[2-(4-methyl-5-imidazolyl)methylthio)ethyl]thioureahydrobromide (from 3.45 g of the thiourea) with 1,4-dibromobutane (1.62g) by the method described in Example 9 afforded the title compound (3.8g), m.p. 185°-187° (from ethanol).

(Found: C, 28.7: H, 4.6: N, 13.4: Br, 38.2: S, 15.1: C₂₀ H₃₄ N₈ S₄. 4HBr requires: C, 28.7: H, 4.6: N, 13.4: S, 38.1: S, 15.3%).

EXAMPLE 12

When 1,8-diaminooctane is substituted for 1,2-diaminoethane in theprocedure of Example 1(c),1,8-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)thioureido]octaneis produced. When 1,8-diaminooctane is substituted for1,3-diaminopropane in the procedure of Example 5(ii),1,8-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]octaneis produced.

When 1,6-diaminohexane is substituted for 1,2-diaminoethane in theprocedure of Example 1(c),1,6-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)thioureido]hexaneis produced. When 1,6-diaminohexane is substituted for1,3-diaminopropane in the procedure of Example 5(ii),1,6-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]hexaneis produced.

EXAMPLE 13

When 1,6-dibromohexane or 1,8-dibromooctane are substituted for1,2-dibromoethane in the procedure of Example 9 the products are1,6-bis-[S-(N-2-(5-methyl-4-imidazolylmethylthio)ethyl)isothioureido]hexaneand1,8-bis-[S-(N-2-(5-methyl-4-imidazolylmethylthio)ethyl)isothioureido]octane,respectively.

EXAMPLE 14

Reaction of 4-methyl-5-(2-aminoethyl)thiomethyl)imidazole with:

(a) N-methanesulphonyliminodithiocarbonic acid dimethyl ester

(b) N-p-toluenesulphonyliminodithiocarbonic acid dimethyl ester

(c) N-benzenesulphonyliminodithiocarbonic acid dimethyl ester

(d) N-trifluoromethanesulphonyliminodithiocarbonic acid dimethyl esterin ethanol at room temperature gave the correspondingS-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-N'-sulphonylthiouroniumderivatives which were treated with 1,3-diaminopropane according to thegeneral procedure of Example 5(ii) to give:

(a)1,3-bis-[N'-methanesulphonyl-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino]propane

(b)1,3-bis-[N'-toluenesulphonyl-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino]propane

(c)1,3-bis-[N'-benzenesulphonyl-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl-guanidino]propane

(d)1,3-bis-[N'-trifluoromethanesulphonyl-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino]propane

EXAMPLE 151,3-bis-[N'-Sulphamyl-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]propane

1,3-bis-[N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl)guanidino]propanedihydrochloride (2.7 g) was added to a solution of sodium (0.46 g) inethanol (50 ml) and the mixture was warmed and stirred for 0.5 hours,cooled and filtered. N-Piperidylsulphamide (1.64 g) was added to thefiltrate which was heated under reflux for 24 hours. The mixture wasconcentrated and purified by chromatography to give the title compound.

EXAMPLE 161,3-bis-[N'-Hydroxy-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]propane

(a) Dry hydrogen chloride was bubbled through a solution of1,3-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)thioureido]propanein methanol at 80° for 12 hours, and the solvent was removed to give1,3-bis[S-methyl-N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)isothioureido]propanetetrahydrochloride.

(b) The bis-isothiourea prepared above was treated with hydroxylaminehydrochloride and potassium hydrogen carbonate in dry dimethylformamideat 85° under an atmosphere of nitrogen to yield the title product.

EXAMPLE 171,3-bis-[N'-Methyl-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]propane

1,3-bis-[S-Methyl-N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)isothioureido]propanetetrahydrochloride was heated with methylamine in methanol to give thetitle product.

EXAMPLE 18

Substitution of:

(a) 4-bromo-5-[(2-aminoethyl)thiomethyl]imidazole

(b) 4-[(2-aminoethyl)thiomethyl]imidazole

(c) 2-[(2-aminoethyl)thiomethyl]thiazole

(d) 3-[(2-aminoethyl)thiomethyl]isothiazole

(e) 3-chloro-2-[(2-aminoethyl)thiomethyl]pyridine

(f) 3-hydroxy-2-[(2-aminoethyl)thiomethyl]pyridine

(g) 3-methyl-2-[(2-aminoethyl)thiomethyl]pyridine

for 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole in the procedure ofExample 1(a) followed by treatment of the product according to thegeneral procedure of Examples 1(b) and 2 gave:

(a)1,3-bis[N'-(2-(5-bromo-4-imidazolylmethylthio)ethyl)thioureido]propane

(b) 1,3-bis[N'-(2-(4-imidazolylmethylthio)ethyl)thioureido]propane

(c) 1,3-bis[N'-(2-(2-thiazolylmethylthio)ethyl)thioureido]propane

(d) 1,3-bis[N'-(2-(3-isothiazolylmethylthio)ethyl)thioureido]propane

(e) 1,3-bis[N'-(2-(3-chloro-2-pyridylmethylthio)ethyl)thioureido]propane

(f)1,3-bis[N'-(2-(3-hydroxy-2-pyridylmethylthio)ethyl)thioureido]propane

EXAMPLE 19

Substitution of the following amines:

(a) 2-[2-aminopropylthio]oxazole

(b) 3-[(2-aminoethyl)thiomethyl]isoxazole

(c) 3-[(2-aminoethyl)thiomethyl]pyrazole

(d) 3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole

(e) 5-amino-2-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole

(f) 2-[(2-aminoethyl)thiomethyl]pyrimidine

(g) 2-[(2-aminoethyl)thiomethyl]pyrazine

(h) 3-[(2-aminoethyl)thiomethyl]pyridazine

(i) 1-methyl-2-[(2-aminoethyl)thiomethyl]imidazole

(j) 2-[(2-aminoethyl)thiomethyl]imidazole

for 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole in the procedure ofExample 1(a) followed by treatment of the products according to thegeneral procedure of Examples 1(b) and 2 results in the production ofthe following products

(a) 1,3-bis[N'-(2-(2-oxazolylthio)propyl)thioureido]propane

(b) 1,3-bis[N'-(2-(3-isoxazolylmethylthio)ethyl)thioureido]propane

(c) 1,3-bis[N-(2-(3-pyrazolylmethylthio)ethyl)thioureido]propane

(d) 1,3-bis[N-(2-(3-(1,2,4-triazolyl)methylthio)ethyl)thioureido]propane

(e)1,3-bis[N-(2-(5-amino-2-(1,3,4-thiadiazolyl)methylthio)ethyl)thioureido]propane

(f) 1,3-bis[N-(2-(2-pyrimidylmethylthio)ethyl)thioureido]propane

(g) 1,3-bis[N'-(2-(2-pyrazolylmethylthio)ethyl)thioureido]propane

(h) 1,3-bis[N'-(2-(3-pyridazolylmethylthio)ethyl)thioureido]propane

(i)1,3-bis[N'-(2-(1-methyl-2-imidazolylmethylthio)ethyl)thioureido]propane

(j) 1,3-bis[N'-(2-(2-imidazolylmethylthio)ethyl)thioureido]propane

EXAMPLE 20

(a) (i) A solution of 4-(2-aminoethyl)thiomethyl)imidazole (6.0 g) andbenzoyl isothiocyanate (6.0 g) in chloroform (150 ml) was heated underreflux for one hour. Concentration followed by recrystallisation fromethyl acetate-isopropyl acetate affordedN-benzoyl-N'-(2-(4-imidazolylmethylthio)ethyl)thiourea (7.5 g). Ananalytically pure sample (from aqueous isopropyl alcohol) had m.p.126°-128°.

(ii) The benzoyl thiourea (6.0 g) was added to a solution of potassiumcarbonate (1.4 g) in water (80 ml) at 60°. The solution was maintainedat this temperature for one hour, concentrated to low bulk and acidifiedwith hydrochloric acid. Benzoic acid was removed by filtration and thefiltrate was basified with potassium carbonate and concentrated underreduced pressure. Following extraction with isopropyl alcohol andconcentration, the product was crystallised from isopropyl acetate.Recrystallisation from water gaveN-(2-(4-imidazolylmethylthio)ethyl)thiourea (2.5 g) m.p. 135°-7°.

(Found: C, 38.9; H, 5.5; N, 26.1; S, 29.6; C₇ H₁₂ N₄ S₂ requires: C,38.9; H, 5.6; N, 25.9; S, 29.6%).

(b) Substitution of

(a) 4-bromo-5-[(2-aminoethyl)thiomethyl]imidazole

(b) 4-[(2-aminoethyl)thiomethyl]imidazole

(c) 2-[(2-aminoethyl)thiomethyl]thiazole

(d) 3-[(2-aminoethyl)thiomethyl]isothiazole

(e) 3-chloro-2-[(2-aminoethyl)thiomethyl]pyridine

(f) 3-hydroxy-2-[(2-aminoethyl)thiomethyl]pyridine

(g) 3-methyl-2-[(2-aminoethyl)thiomethyl]pyridine

for 4-(2-aminoethyl)thiomethyl)imidazole in the above procedure andtreatment of the products according to the general procedure of Example5 gives

(a)1,3-bis[N'-(2-(5-bromo-4-imidazolylmethylthio)ethyl)guanidino]propane

(b) 1,3-bis[N'-(2-(4-imidazolylmethylthio)ethyl)guanidino]propane

(c) 1,3-bis[N'-2-(2-thiazolylmethylthio)ethyl)guanidino]propane

(d) 1,3-bis[N'-(2-(3-isothiazolylmethylthio)ethyl)guanidino]propane

(e) 1,3-[N'-(2-(3-chloro-2-pyridylmethylthio)ethyl)guanidino]propane

(f) 1,3-bis[N'-(2-(3-hydroxy-2-pyridylmethylthio)ethyl)guanidino]propane

EXAMPLE 21

Treatment of:

(a) 2-[2-aminopropylthio]oxazole

(b) 3-[(2-aminoethyl)thiomethyl]isoxazole

(c) 3-[(2-aminoethyl)thiomethyl]pyrazole

(d) 3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole

(e) 2-[(3-aminopropylthio]pyrimidine

(f) 2-[(2-aminoethyl)thiomethyl]pyrazine

(g) 3-[(2-aminoethyl)thiomethyl]pyridazine

(h) 1-methyl-2-[(2-aminoethyl)thiomethyl]imidazole

(i) 2-[(2-aminoethyl)thiomethyl]imidazole

according to the general procedure of Example 20 gives:

(a) 1,3-bis[N'-(2-(2-oxazolylthio)propyl)guanidino]propane

(b) 1,3-bis[N'-(2-(3-isoxazolylmethylthio)ethyl)guanidino]ppropane

(c) 1,3-bis[N'-(2-(3-pyrazolylmethylthio)ethyl)guanidino]propane

(d) 1,3-bis[N-(2-(3-(1,2,4-triazolyl)methylthio)ethyl)guanidino]propane

(e) 1,3-bis[N-(3-(2-pyrimidylthio)propyl)guanidino]propane

(f) 1,3-bis[N'-(2-(3-pyrazolylmethylthio)ethyl)guanidino]propane

(g) 1,3-bis[N'-(2-(3-pyridizylmethylthio)ethyl)guanidino]propane

(h)1,3-bis[N'-(2-(1-methyl-2-imidazolylmethylthio)ethyl)guanidino]propane

(i) 1,3-bis[N'-(2-(2-imidazolylmethylthio)ethyl)guanidino]propane

EXAMPLE 22

Substitution of:

(a) 4-(4-aminobutyl)imidazole

(b) 4-(4-aminobutyl)-5-methylimidazole

(c) 4-(4-aminobutyl)-5-bromoimidazole

(d) 4-(4-aminobutyl)thiazole

for 4-methyl-5-(2-aminoethyl)thiomethyl)imidazole in the procedure ofExample 1(a) followed by treatment of the product according to thegeneral procedure of Examples 1(b) and 2 gave:

(a) 1,3-bis-[N'-4-(4-imidazolylbutyl)thioureido]propane

(b) 1,3-bis-[N'-4-(5-methyl-4-imidazolylbutyl)thioureido]propane

(c) 1,3-bis-[N'-4-(5-bromo-4-imidazolylbutyl)thioureido]propane

(d) 1,3-bis-[N'-4-(4-thiazolylbutyl)thioureido]propane.

EXAMPLE 23

Treatment of:

(a) 4-(4-aminobutyl)imidazole

(b) 4-(4-aminobutyl)-5-methylimidazole

(c) 4-(4-aminobutyl)-5-bromoimidazole

(d) 4-(4-aminobutyl)thiazole

according to the general procedure of Example 20 gives:

(a) 1,3-bis-[N'-4-(4-imidazolylbutyl)guanidino]propane

(b) 1,3-bis-[N'-4-(5-methyl-4-imidazolylbutyl)guanidino]propane

(c) 1,3-bis-[N'-4-(5-bromo-4-imidazolylbutyl)guanidino]propane.

(d) 1,3-bis-[N'-4-(4-thiazolylbutyl)guanidino]propane

EXAMPLE 241-[N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl)guanidino]-3-[N'-(2-(2-thiazolylmethylthio)ethyl)thioureido]propane

(a) (i) 3-Benzoylaminopropylamine was treated successively with carbondisulphide and methyl iodide according to the general procedure ofExample 1(a)(b) to give S-methyl-N-(3-benzoylaminopropyl)dithiocarbamatehydriodide.

(ii) The above hydriodide was treated with one equivalent of sodiumethoxide and 2[(2-aminoethyl)thiomethyl]thiazole, and the product washydrolysed with acid to giveN-(3-aminopropyl)-N'-(2-(2-thiazolylmethylthio)ethyl)thiourea.

(iii) The above thiourea was heated under reflux for 2 hours with anaqueous solution ofS-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiouroniumsulphate in water. The mixture was concentrated and purified bychromatography to give the title compound.

(b) (i) 2-[(2-Aminoethyl)thiomethyl]thiazole was successively treatedwith carbon disulphide and methyl iodide according to the generalprocedure of Example 1(a)(b) to giveS-methyl-N-[2-(2-thiazolylmethylthio)ethyl]dithiocarbamate hydriodide.

(ii) The above hydriodide was treated with one equivalent of sodiumethoxide and 3-benzoylaminopropylamine and the product was hydrolysedwith acid, and subjected to the procedure (a) (iii) above, to give thetitle compound.

EXAMPLE 25 1,3-bis-[N'-(2-(4-imidazolylethylthio)ethyl)guanidino]propane

When 4-[2-(2-aminoethyl)thioethyl]imidazole is subjected to the generalprocedure of Example 20 the title compound is produced.

EXAMPLE 261,3-bis-[N'-Carbamoyl-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]propane

Treatment of1,3-bis-[N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]propanewith dilute hydrochloric acid at 40° yielded the title product.

EXAMPLE 271,3-bis-[1-[2-((5-Methyl-4-imidazolyl)methylthio)ethylamino]-2-nitrovinylamino]propane

A solution of1-nitro-2-methylthio-2-[2-(5-methyl-4-imidazolyl)methylthio)ethylamino]ethylene(2.0 g) and 1,3-diaminopropane (0.26 g) in ethanol (10 ml) was heatedunder reflux for 2 hours. The product was purified on an ion-exchangeresin (GC 50 (H⁺)), by elution with 0.012 N hydrochloric acid andfinally chromatographed on a column of silica gel to yield the titlecompound.

EXAMPLE 281-[1-(2-((5-Methyl-4-imidazolyl)methylthio)ethylamino)-2-nitrovinylamino]-3-[N'-cyano-N"-(2-(2-pyridylmethylthio)ethyl)guanidino]propane

1-Nitro-2-methylthio-2-[2-((5-methyl-4-imidazolyl)methylthio)ethylamino]ethylenewas reacted with 3-benzoylaminopropylamine and the product washydrolysed under acidic conditions and reacted withN-cyano-N'-[2-(2-pyridylmethylthio)ethyl]-S-methylisothiourea to givethe title compound.

EXAMPLE 29

    ______________________________________                                        Ingredients            Amounts                                                ______________________________________                                        1,3-bis-[N'--(2-(5-Methyl-4-imidazolyl-                                                              150 mg.                                                methylthio)ethyl)guanidino]propane                                            dihydrochloride                                                               Sucrose                75 mg.                                                 Starch                 25 mg.                                                 Talc                   5 mg.                                                  Stearic Acid           2 mg.                                                  ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 30

    ______________________________________                                        Ingredients            Amounts                                                ______________________________________                                        1,3-bis-[N'--(2-(5-Methyl-4-imidazolyl-                                                              200 mg.                                                methylthio)ethyl)guanidino]propane                                            dihydrochloride.                                                              Lactose                100 mg.                                                ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

What is claimed is:
 1. A compound of the formula: ##STR24## wherein R₁and R₂, which are the same, each represent a grouping of the structure:

    Het--(CH.sub.2).sub.m Z--(CH.sub.2).sub.n --

wherein Het is a nitrogen containing 5 or 6 membered heterocyclic ringselected from thiadiazole, pyrimidine, pyrazine or pyridazine which isoptionally substituted by lower alkyl, hydroxyl, halogen or amino; Z issulphur or a methylene group; m is 0, 1 or 2; n is 2 or 3 and the sum ofm and n is 3, 4 or when Y is other than hydrogen, methyl, or hydroxyl,2; X₁ and X₂, which may be the same or different, are each sulphur,CHNO₂ or NY wherein Y is hydrogen, hydroxy, lower alkyl, cyano, CONH₂ orSO₂ R₃ ; R₃ is lower alkyl, phenyl, tolyl, trifluoromethyl or amino; Wis NH, and when X₁ and X₂ are NH, W may also be sulphur; and q is aninteger from 2 to 8; or a pharmaceutically acceptable acid addition saltthereof.
 2. A compound according to claim 1 wherein W is NH.
 3. Acompound according to claim 2 wherein X₁ and X₂, which may be the sameor different, are each sulphur or NY and wherein Y is defined inclaim
 1. 4. A compound according to claim 1 wherein Z is sulphur m is 1and n is
 2. 5. A compound according to claim 1 wherein X₁ and X₂ are thesame.
 6. A compound according to claim 5 wherein X₁ and X₂ are bothsulphur, NH or NCN.
 7. A compound according to claim 5 wherein X₁ and X₂are both CHNO₂.
 8. A compound according to claim 1 wherein q is from 2to
 4. 9. A compound according to claim 8 wherein q is
 3. 10. Apharmaceutical composition to inhibit H-2 histamine receptors, said H-2histamine receptors being those histamine receptors which are notinhibited by mepyramine but are inhibited by burimamide, comprising, inan effective amount to inhibit said receptors, a compound of claim 1 incombination with a pharmaceutically acceptable diluent or carrier.
 11. Amethod of inhibiting H-2 histamine receptors, said H-2 histaminereceptors being those histamine receptors which are not inhibited bymepyramine but are inhibited by burimamide, which comprisesadministering orally or parenterally to an animal in need thereof in aneffective amount to inhibit said receptors a compound of claim 1.